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,Eji| m ■ % ^ | Addiction: Diseased Brain, H E X Divided Will, or Restless Heart?

Judith A. Judith A. Toronchuk Toronchuk ’

Addictive disorders lay a heavy burden on global medical resources while continu­ ing to devastate personal lives at an alarming rate. Complex interrelated risk factors, including biological, psychological, sociological, cultural, and spiritual factors, must be considered as churches and communities address the individual and societal problems. This article will consider multiple causes of substance and behavioral addiction and reflect on the issue of determinism versus free zvill. I will take the position that addicts, as all persons, are simultaneously constrained by their embodied nature and yet free to respond to God's grace. The disease model and the choice model are not in opposition: rather, the brain changes that occur during addiction give rise to habits and compul­ sions which, nevertheless, can be broken as new habits are formed through both divine grace and grace offered by supportive others. M ultiple approaches are needed to address a multifactorial problem.

A ddiction rates around the world continue unabated while church, society, and individuals struggle to respond in an efficacious manner. Since 2014, the US and Canada have had the highest per capita consumption of opioids (combined prescription and illicit) in the world. The addiction and overdose bur­ den primarily afflicts young males; in the US in 2016, opioids were responsible for 20% of deaths among those aged 24 to 35.1 The US Centers for Disease Control and Prevention (CDC) reports that tobacco use in the US remains the leading preventable cause of disease, disability, and death — contributing to one in every five deaths.2 Globally, the World Health Organization (WHO) estimated that, in the twentieth century, 180 million people were killed by tobacco.3 Why do people choose to endanger their health, livelihood, family, and even life itself to consume addictive substances?

Judith A. Toronchuk holds a PhD in physiological psychology from McGill University and a M A of Theological Studies from Regent College. She taught neuroscience and psychology at Trinity Western University for over twenty years, has published on sensory physiology and affective neural systems, and served on both the ASA and CSCA Executive Councils.

Addictive behavior illustrates the age- old ontological conundrum of whether human behavior is essentially deter­ mined, at various levels and by multiple factors, or freely engaged in by the indi­ vidual. The disease model, supported by substantial neurophysiological research, states that substance addictions4 are recur­ ring disorders of the brain, originating in genetic components and neuroplasticity.5 Evidence is now accumulating that an entire spectrum of behaviors —includ­ ing compulsive gambling, eating, and viewing of pornography — have under­ lying genetic and neural similarities with substance abuse.6 However, because not all users develop addiction, and most addictions remit without treatment, this medical model has been called into doubt by those who stress psychosocial and environmental influence as well as spiri­ tual and moral factors.7 In this article, we will discuss each of these factors in turn and attempt a holistic response.

Neural Mechanisms of Addiction For organisms to learn and successfully repeat behaviors that result in survival of

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the individual and the species, certain brain mecha­ nisms for motivation, emotion, and executive control must be activated.8 Substance abuse occurs when these normal mechanisms become overwhelmed due to repeated, supranormal phasic activation by particular external substances. Pleasurable behaviors including eating, drinking, music, video games, and social and sexual interactions are all accompanied by release of the neurotransmitter dopamine in the nucleus accumbens (NAc), a small subcortical area in the ventral striatum which codes for salience of rewards and reward cues. This area, part of the lim­ bic system, is rich in dopamine receptors, and it sends output to forebrain areas responsible for attention, memory, and executive control. The current view of most researchers is that most abused substances pro­ mote, by direct or indirect means, rapid phasic bursts of dopamine release three to five or more times greater than that provided by nonaddictive reinforc­ ers which produce more tonic release.9 The universal dopamine theory of addiction is the most prevalent theory among researchers, although others propose that addiction involves disruptions of multiple trans­ mitters and that different drugs produce different neural adaptations as discussed below.10

Dopamine release in NAc flags an event as worth attending to and the cues associated with it as worth learning so that the rewarding behavior may be repeated. After it was discovered in 1954 that rats will press a lever thousands of times per hour to receive electrical stimulation at this location in the brain, it was proposed that the NAc was a "plea­ sure center," but this is now seen as too simplistic. The ability to learn and remember the salient cues predicting rewards depends on an extensive neural pathway which extends from the midbrain ventral tegmental area (VTA) where dopaminergic neurons originate, to the NAc where dopamine is released, then to the orbitofrontal cortex which participates in evaluation and executive control, and finally to other structures involved in memory and emotions. Dopamine released by VTA axons into synapses in NAc attaches briefly to receptors on NAc neurons and then is rapidly taken up again into the releasing axons by means of molecular transporter molecules.11 Cocaine blocks these transporter molecules, whereas amphetamine and its derivatives cause the trans­ porters on the dopaminergic axons to run in reverse. In either event, the dopamine available in the syn­ apse to stimulate the postsynaptic cell is increased.

Reward has both "wanting" and "liking" compo­ nents because, as addicts come to realize, one can "want" something that one does not really "like"; thus the NAc should not be simplistically referred to as the brain's "pleasure center."

Dopamine release in NAc produces "wanting" rather than "liking" by focusing attention on the stimuli already associated with reward.12 At the same time, the memory of reinforcement causes decreased activ­ ity in the frontal cortical executive circuits which normally provide inhibitory control over behavior.13 The most recent hypothesis is that dopamine release is time-locked to unexpected or novel stimuli and acts as a reward prediction signal.14 This mechanism underlies learning of the behaviors necessary to provide a mammal with food, drink, and social part­ ners, and results in the long-term structural changes in synapses which normally underlie learning. The mechanism functions as it should if the organism learns, for example, where food is available and repeats whatever behavior procured it. The problem arises when supraphysiological bursts of dopamine produced by addictive substances cause attention, emotion, and motivation to focus exclusively on drug-related cues. Psychostimulants such as cocaine, methamphetamine, MDMA, and "bath salts" directly affect the NAc.15 The increased bursting activity pro­ duced by these drugs is necessary and sufficient on its own to promote reinforcement directly. Evidence indicates that indirect processes, reviewed below, which often involve endogenous opioid or cannabi- noid receptors, are needed to indirectly activate the dopamine response to the presence of opiates, etha­ nol, cannabis, and nicotine.16 Dopamine is of primary importance in stimulant addiction and cue-triggered craving for opioids, but perhaps the endogenous opiates and GABA17 systems play the primary role in producing satisfaction ("liking" as opposed to "wanting") in opioid and cannabis addiction.18

Nonaddictive behaviors cause the slow, lengthy release of dopamine in NAc, stimulating high affinity D2 receptors which sustain moderate levels of moti­ vation necessary to procure and consume rewards.19 Large rapid bursts of dopamine stimulate both D2 and lower affinity D1 receptors which signal expec­ tation of reward and cause drug "highs." Activity in the midbrain VTA itself is influenced by reciprocal innervation from widespread limbic and lower-level areas involved in memory, emotion, attention, and

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motivation. Most cells in the NAc also receive mul­ tiple varied inputs regarding stimulus salience from widespread limbic areas via dopamine, glutamate, endocannabinoids, and other inputs. Conditioning to salient cues can be induced by dopamine bursts large enough to activate the D1 receptors. Stimuli associated with the drug thus become conditioned and eventually trigger phasic release of dopamine from VTA onto the NAc. The VTA neurons are themselves normally under tonic inhibition due to the transmitter GABA.20 The timing of dopamine bursts is likely controlled by VTA local interneurons and other GABA-releasing axons from those ventral brain regions, subject to neuroplastic changes, which are involved in evaluation of rewards, attention, arousal, and memory. Among the changes in the brain associated with repeated drug use are altered firing patterns in VTA and its input areas due to cel­ lular-level mechanisms which normally accompany learning.

Endogenous opioids (including endorphins) and endogenous cannabinoids (endocannabinoids) inter­ act in complex ways with the dopamine system in natural and drug-produced hedonic responses along with additional transmitters, many involved in eating and satiety.21 In addition, the release of dopa­ mine is increased by glutamate released in the VTA by dorsal raphe cells.22 Serotonin (5-HT) from dor­ sal raphe cells also plays a lesser but more complex role. One type of serotonin receptor23 (5-HT2C) in the VTA seems to decrease stimulant-induced reinforce­ ment, while another (5-HT1B) indirectly increases dopamine release by disinhibition of GABAa receptors.24 Endogenous opioids and endogenous cannabinoids also interact in complex ways with the dopamine system in natural and drug-produced hedonic responses. Other transmitters and modula­ tors involved in natural rewards, including leptin, insulin, galanin, neuropeptide Y, substance P, and melanocortins, also influence the system. Many of these substances are involved in regulation of eating. In summary, the control of dopamine release is com­ plicated and much more research will be necessary to paint a complete picture.

Opiate drugs, including heroin, fentanyl, and oxy­ codone, stimulate opioid receptors directly. Most opioid abusers start with prescription drugs but soon discover less expensive alternatives on the street.25 When prescriptions run out or are limited,

users often turn to cheaper illicit drugs such as her­ oin. However, fentanyl is even cheaper than heroin, and users are often unaware that what they buy on the street as heroin or oxycodone may be substan­ tially fentanyl.26 Fentanyl, in combination with street drugs, was responsible for over 80% of the more than 1,420 overdose deaths in British Columbia in 2017.27 Synthetic opioids mimic the effects of these neuromodulatory endogenous opioids by binding to |i opioid receptors, which are plentiful in both VTA and NAc.28 One effect of p receptor stimulation is to release the "brakes" in the VTA by disinhibiting nor­ mal inhibitory modulation GABAergic neurons in the VTA, which in turn disinhibit dopamine release in the NAc. Most of the reinforcing effects of opioid drugs are due to direct stimulation of p receptors on the NAc cells. Naturally occurring endorphins decrease sensitivity to pain, increase relaxation, and cause drowsiness by blocking the brainstem area (locus coeruleus) that responds to arousing stim­ uli. Hence, opioids reduce both anxiety and pain, and normally function to promote positive feelings brought on by contact and social interaction. The effect that endorphins have on cortical emotional systems helps explain why relational loss is per­ ceived in humans as similar to pain and panic. Social pain in humans, separation distress in animals, and the affective component of physical pain all involve the anterior cingulate cortex and the insula; further­ more, g opioid receptors are implicated in each of these types of pain.29

Alcohol use disorders are among the most common mental disorders, with 36% of adult males in the US meeting the criteria for the disorder at some time in their lives.30 Ethanol has widespread complex inter­ actions with GABA, serotonin (5-HT), endorphins, endocannabinoids, glutamate, and nicotinic recep­ tors, although the major contributor to pleasurable sensations is the mesolimbic dopamine system. It also acts on the inhibitory GABA interneurons which normally act as "brakes" controlling VTA cells, thereby indirectly producing increased release of dopamine in NAc.31 Ethanol's facilitation of the inhibitory transmitter GABA in widespread areas of the brain leads to muscle relaxation, decreased anxi­ ety, decreased behavioral inhibition, and eventually loss of consciousness. Stress-related circuits, includ­ ing those of corticotropin-releasing hormone (CRH) and neuropeptide Y, are also eventually affected, contributing to the adverse effects of ethanol with-

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drawal by producing anxiety and depression. In adolescents, alcohol alters the development of grey and white matter and disrupts pathways involved in attention, verbal learning, visuospatial processing, and memory. In rodents, this causes decreased cog­ nitive flexibility, behavioral inefficiency, increased anxiety, impulsivity, and risk-taking, as well as impaired neurogenesis and epigenetic alterations as further discussed below.32

The main psychoactive ingredients in cannabis are A-9-tetrahydrocannabinol (A-9-THC) and cannabidiol (CBD) which mimic the effects of endocannabinoids at their receptor sites.33 Cannabiniod receptors are one of the most abundant receptors occurring throughout the brain, and activation produces a variety of effects on hunger, nausea, memory, sen­ sation, and subjective perception of time. Similar to endocannabinoids, A-9-THC is believed to indi­ rectly decrease inhibition on dopaminergic neurons by inhibiting GABA release in the VTA. After pro­ longed use, synaptic plasticity required for encoding of memory can be disrupted, and therefore learning can be impaired, especially during periods of brain development or reorganization.34 A-9-THC also has psychoactive effects and increases anxiety, whereas CBD can facilitate learning and reduce anxiety, and when taken together with A-9-THC may ame­ liorate its harmful effects, especially on memory. Unfortunately, the levels of A-9-THC in street can­ nabis has risen threefold over the last twenty years while that of CBD has declined to negligible levels. Legalization has been suggested as a way to stan­ dardize and control the ratio of A-9-THC to CBD and therefore reduce possible harms caused by cannabis.35

Endocannabinoids affect neurodevelopment by interacting directly with the glutamate pathways which play a major role in two processes prevalent during adolescence —the development of axonal connections and the process of pruning irrelevant synapses. Adolescent exposure to A-9-THC thus alters the normal maturational fluctuations of the glutamate receptors which underlie learning mecha­ nisms, leading to decreases in dopamine activity in adulthood and to increased levels in stress-related signaling. In regular cannabis users, the hippocam­ pus (involved in long-term memory) has decreased volume, although CBD in addition to A-9-THC may ameliorate this effect.36 Neuroimaging studies also

reveal decreased volume in the orbitofrontal cor­ tex, a major area for executive control.37 Because the effects of cannabis on cognition seem dependent on the maturational state of the brain, adolescents appear to be the most vulnerable to neural changes.38 The present consensus is that cannabis has addictive potential, although the risk of dependence after first exposure has been reported at 8.9%, compared with higher rates of 20.9% for cocaine, 22.7% for alcohol, and 67.5% for nicotine.39 Although statistics on long­ term use of cannabis are not clear, lower addictive potential than alcohol or tobacco, and hence less- compulsive use suggests lower mortality.

Nicotine, despite its high-addictive potential in humans, differs from most other drugs in that it produces reinforcement without euphoria and is less strongly reinforcing in animals.40 It activates the hypothalamic-pituitary-adrenal (HPA) axis which governs the body's stress response and can block pain from the stimulation of nerve cells. Nicotine directly stimulates certain types of acetylcholine receptors and, depending on the site of action and subtype of receptor, alters release of dopamine, norepinephrine, serotonin, glutamate, GABA, and endogenous opioids.41 Stimulation of a4(32 subunits of the nicotinic receptors on dopaminergic neurons in NAc contributes to the rewarding effect. The endorphin/p opioid system, glutamate, and endo- cannabinoid systems are also implicated. Consistent with reports that stress increases cigarette smoking, activation of the dynorphin/x opioid system associ­ ated with stress and negative states may be involved in nicotine dependence and withdrawal.42 The opioid antagonist naltrexone decreases nicotine use, further supporting the hypothesis that endogenous opioids contribute to nicotine reinforcement.

Behavioral Addictions The neurophysiological mechanisms for uncontrolled gambling, internet use, gaming, pornography, and sexual acting out have been shown to be remarkably similar to those elicited in psychoactive substance abuse. Obesity, overeating, and compulsive shop­ ping are now being researched along these lines.43 Many of these behavioral disorders share similarities with substance abuse, including preexisting vulner­ abilities due to failed regulation of the mesolimbic dopamine system by frontal regions. Dopamine agonists can trigger in some Parkinson's patients

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compulsive gambling, sex, and shopping, further suggesting that dopamine dysregulation may be involved in these behaviors. Even the intense eupho­ ria and attentional focus of romantic relationships share many facets of addiction because the basic cir­ cuitry for romantic love and attachment necessary for survival of the species shares the same circuitry co-opted by drugs.44 Is it possible that there is a continuum which stretches from normal, necessary behaviors of eating, romantic love, attachment, and social behavior, through mildly disordered behav­ iors, which then finally ends in the disfunctionality of addiction? If so, this might mean that addiction, rather than being a disease afflicting only some, is a risk factor carried by all.

Gambling disorder (GD) is the first nonsubstance disorder classified by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5 in the category of "Substance-Related and Addictive Disorders." Both D2 and p opioid receptors are implicated in GD, and opioid antagonists such as naloxone are the most promising drugs of treatment. As with drug abuse, deficits exist in executive functions, decision mak­ ing, and inhibitory control because of diminished activation of the ventromedial prefrontal cortex con­ trol mechanisms.45 Similarly, fixations, tolerance, and withdrawal also occur. The heritability of pathologi­ cal gambling, estimated from twin studies, is similar to alcohol and drug abuse. GD also shares genetic vulnerability factors with antisocial behaviors, alco­ hol dependence, and major depressive disorder, as well as having a 96% comorbidity rate with lifetime psychiatric disorder.

Obsessive and compulsive eating share disruptions in transmitter and hormone systems, which again overlap normal systems for food reward and the disordered systems associated with drug reward.46 Chocolate cravers show greater activation in many reward areas which are also activated in drug crav­ ing. Dopamine release in the NAc varies as a function of food palatability, and an inverse relationship has been reported between D2 receptors and BMI.47 One suggestion is that reduced dopamine levels occur in the obese, promoting overeating of highly palat­ able foods as compensation for reward deficiency. Endocannabinoid and endorphin systems normally interact with the dopamine system to help regulate food intake. Furthermore, chemical signals involved in normal satiety and hunger (i.e., leptin, insulin,

ghrelin) not only influence the sensitivity of the brain dopamine system to the rewarding effects of food, but also modulate sensitivity to the rewarding effects of various drugs.48 The rewarding effects of foods, particularly those rich in fat and sugar, can trigger neuroadaptations in brain reward, stress circuitry, and prefrontal control systems that are similar to those produced by addictive drugs. As stated above, mechanisms which evolved for survival are difficult for most people to control.

Internet gaming disorder is included in the current diagnostic manual, DSM-5, under the heading of "Conditions for Further Study." William Struthers presents the case for the addictive properties of inter­ net pornography,49 but other internet activities such as cybersex, online relations, shopping, and surfing may also be addictive. The findings for all the inter­ net disorders are consistent with neuroimaging and with neurobiological and psychological models of substance disorder.50 Game-related pictures elicit fMRI activation patterns in both NAc and in the orbitofrontal cortex of heavy-internet-gaming users that are similar to those found in substance abusers. Grey matter reductions in orbitofrontal regions and alterations in the dopamine system have also been reported in excessive internet gaming users.

Genetic and Epigenetic Influences Genetic variations in the dopamine system have been correlated with substance abuse, obesity, pathological gambling, and several other disor­ ders.51 Neuroimaging studies show that individuals with lower density of D2 receptors find stimulant drugs more pleasant than those with high density. Nevertheless, not all of these low-density people become addicted, and fully 33% of all people have the allele associated with addiction. One puzzling question is why some users of drugs, alcohol, and tobacco become dependent, but others do not. Exact incidence varies with the type of substance, but only about 10% of individuals using illegal drugs or alco­ hol become addicted, even though 30%-70% of that risk may be attributable to genetics.52 As discussed in this issue by Robin Rylaarsdam, because large numbers and combinations of genes, plus epigenetic factors, are implicated, it is difficult to identify spe­ cific addiction-related alleles and any one allele may increase a person's risk factor by only a very small percentage.53

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Genetic coding influences drug risk via two types of mechanisms: (1) the psychoactive effects are influenced by receptors; and (2) the ability to metab­ olize external substances is controlled by enzymes. Variants of GABA receptors may be implicated in many sorts of addictions, including alcohol. The risk for nicotine addiction is increased by numerous polymorphisms in the genes that encode the various nicotinic receptor subunits. Genetic variants of the p opioid receptor have been found which modulate the effectiveness of the opioid antagonist naltrexone and which are also associated with relapse of alco­ hol abuse.54 Regarding the second mechanism, a protective factor against alcohol abuse is provided by those variants of the genes for alcohol dehydro­ genase and acetaldehyde dehydrogenase, which result in unpleasant side effects, as Rylaarsdam notes. Nicotine addiction is also affected by variants of genes for the enzyme that breaks down nicotine in the liver.

The term "Reward Deficiency Syndrome" (RDS) was coined in 1996 to suggest that genetic differences in the dopamine receptor system might be involved in addiction and impulsive disorders.55 Carriers of the A1 allele of the D2 receptor gene have 30%-40% fewer D2 receptors available for dopamine signal­ ing. Dysfunction in the dopamine receptor system has been associated with several disorders, includ­ ing alcohol and substance abuse, obesity, and pathological gambling. Neuroimaging studies show that individuals with lower density of D2 recep­ tors find stimulant drugs more pleasant than those with high density, perhaps due to increased sensi­ tivity caused by fewer receptor sites. Individuals with alcohol-use disorders have reduced levels of D2 receptors in the NAc region, but the causal genetic relationship is not clear. Because D2 recep­ tor levels are also affected by stress (and in monkeys by stress-associated social hierarchies), D2 levels influencing the predisposition to drug use could be epigenetically influenced by environmental factors.56 However, the recurring theme of reduced dopamine activation may explain why most abusers of alcohol have another substance use disorder: at least one-half use tobacco; and one-third, other drugs.57 Clearly the vulnerability to substance abuse is polygenic and influenced by the environment; nevertheless, under­ standing of genetic variations may someday provide useful tools for treatment strategies.

Neuroplasticity in Emotion and Control Circuits: Dividing of the Will? The concept of divided will introduced by Augustine addresses Paul's dilemma in Romans 7:18. As Augustine states it,

This partial willing and partial non-willing is thus not so bizarre, but a sickness of the mind, which cannot rise with its whole self on the wings of truth because it is heavily burdened by habit. There are two wills, then, and neither is the whole: what one has the other lacks.58

This passage from his Confessions echoes the common experience of addicted persons so aptly described as burdened by habit that they often want, but do not want, a drug or behavior. "Wanting" something and "liking" it are not the same, but this is only one example of dual-process thinking. The concept of the divided mind has been popularized by Daniel Kahneman in Thinking, Fast and Slow which char­ acterizes two brain systems: one — unconscious, instinctive, and emotional; and the other—con­ scious, logical, and deliberative.59 Both systems are necessary for normal adult thought, but, in certain situations, the rapid unconscious system gives rise to thought habits which become difficult to break. This insight from Kahneman suggests a useful way to think about addiction in terms of habit driven by unconscious systems.

Repeated use of addictive substances eventually restructures the synaptic pathways from the NAc and VTA, causing an increase in the number of stim­ ulated dendrites, while other usual reinforcers come to stimulate fewer dendrites.60 The incentive salience system of the NAc can motivate for short-term, but not long-term goals. As attention becomes more nar­ rowly focused on the drug, long-term changes occur in motivation, emotion, and executive control. Due to physiological adaptation to the high levels of dopa­ mine, chronic use of a drug often leads to a decrease in the subjective feeling of pleasure, and increasingly greater amounts are necessary to produce the same "high." Eventually substance abusers try to avoid the distress, irritability, and restlessness of the decreased dopamine release by compulsive pursuit of the sub­ stance. Thus changes in motivation are accompanied by changes in emotional mechanisms. The memory of substance reinforcement also decreases activity in the frontal cortical executive circuits that normally

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provide inhibitory control over all adult behavior and allow adults to consciously make wise decisions. Whenever frontal cortex is damaged or its output decreased, the ability to voluntarily regulate behav­ ior becomes impaired. Behavioral control shifts from the prefrontal areas involved in conscious decisions to the dorsal striatum, which is involved in habitual motor patterns.61

Allostatic dysregulation of the reward circuits, along with the recruitment of stress responses, gives rise to addiction through a shift from impulsive action learned via the mechanisms of positive reinforce­ ment, to compulsive action learned through either negative reinforcement or habit formation.62 The initial bursts of dopamine during intoxication cause positive reinforcement, which eventually leads to learning drug cues. The normal molecular basis of learning is based on the repeated activation of syn­ apses, leading to increased efficacy due to long-term facilitation in synapses and dendrites. These normal mechanisms of learning allow cues associated with the drug or behavior to become conditioned and behavioral habits to form.

Following chronic drug use, epigenetic changes occur in gene expression in the NAc, causing increased activation of the gene that codes for dynorphin.63 Unlike other endogenous opiates, dynorphin inhib­ its the VTA and further dopamine release, and it also facilitates anxiety-like states. The VTA then activates the amygdala (associated with fear) leading to nega­ tive emotions, activates stress systems, and decreases sensitivity to natural rewards. Hormones, such as cortisol, that enhance stress responses are released; and the heightened feeling of stress facilitates craving and relapse. Chronic use decreases subjective reward and often leads to tolerance due to adaptation to increased dopamine, necessitating greater amounts of the drug to produce the usual "high." This sensi­ tization to stress is referred to as the "dark side" of addiction because individuals become focused on compulsively seeking more of the drug to prevent withdrawal and irritability. "Wanting" now occurs in the absence of "liking." Eventually longer-term epigenetic changes occur in the brain. Dynorphin then comes to be suppressed during abstinence, and sensitivity returns to the reward path. This new sensitization means that less drug is now needed to activate the mechanisms of "wanting." These epigen­ etic changes can remain for months.64

Depressive disorders and compulsive running also involve similar epigenetic changes. The processing of cue salience and the ability to exert self-control both require dopamine release and the presence of receptors in the prefrontal cortex; however, neuro­ imaging shows reduced dopamine activity in this area in addicts due to reduction in D2 receptors (with the exception of cannabis users).65 Due to impaired prefrontal control, the ability to inhibit risky behav­ iors and delay reward is reduced, and flexibility in making further choices is impaired. This sensitiza­ tion to drug cues can also cause craving in abstinent former users. Cues associated with the drug, such as paraphernalia, places, and people, increase anticipa­ tory activity in the sensitized NAc and related areas and reinstate craving. This mechanism helps explain the increased risk of overdose death when a former addict suddenly uses their previously accustomed dose.

Emotional and motivational systems that evolved to promote survival are difficult to control with conscious effort. Marc Lewis has provided a develop­ mental-learning model of addiction which attempts to bridge the gap between the false dichotomy of disease and choice models.66 Habits form as activity in the NAc restructures and over time strengthens activity in the dorsal striatum (motor program area) and amygdala (emotion center). Axons normally grow from the ventral striatal area of NAc to the dorsal striatum as habits form.67 Automatization of habits frees up cognitive processes for other things, allowing us to drive and talk at the same time. This shift in activation also occurs when an addiction forms. The repetitive strengthening of this pathway over time can lead to habits of drug use and eventu­ ally to compulsion similar to obsessive-compulsive disorder (OCD)—which primarily involves the dor­ sal striatum—as attention becomes modified by drug use and focused on drug cues.68 At the same time, the executive control pathways from the prefrontal cor­ tex become disengaged. These well-researched brain changes lead many researchers to classify addiction as a disease, but Lewis, a developmental neuro­ psychologist, sees it as an extreme form of processes normally used in learning.

These normal modifications of the brain are revers­ ible, leaving open the possibility of unlearning if new habits are formed. Furthermore, as in OCD, these changes occur in pathways below consciousness,

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causing them to seem irrational even to the addict. Augustine wrote of his struggle, "Any sort of habit is bondage."69 Lewis contends that brain changes are normal rather than genetically preprogrammed and depend on feedback from the environment. The mutually reinforcing repetitions of certain behaviors, especially during childhood, also play a role in the development of anxiety and depression. And the brain self-organizes as learning occurs and as habits emerge.

Animals, children, addicts, and those with damaged prefrontal connectivity find delaying rewards diffi­ cult because they have less executive control over the dorsal striatum from the prefrontal cortex than do normal human adults. Adolescence is a time of brain reorganization during which the prefrontal areas are last to develop all their connections. The NAc, amygdala, and dorsal striatum develop earlier than prefrontal areas; this leads to imbalances in activa­ tion during adolescent development.70 Dopaminergic axons continue to grow from the striatum to the pre­ frontal cortex during adolescence, and target choice appears to be malleable.71 Top-down regulation of these striatal areas increases as the frontal cortex develops. The result of this temporary imbalance is that adolescents have even less top-down control of the lower areas associated with emotion, reward, and habit than younger children, leaving them espe­ cially vulnerable to the effects of addictive drugs.

Psychological Factors The neurophysiological and genetic data help explain why addiction is so difficult to treat; how­ ever, we are not fully determined mechanisms, and so other factors must be considered. A study of over 12,000 individuals reported probability estimates of life-time remission from dependence at 84% for nico­ tine, 91% for alcohol, 97% for cannabis, and 99% for cocaine.72 Median time to remittance was 26 years for nicotine, 14 for alcohol, 6 for cannabis, and 5 for cocaine. Although we can describe many risk fac­ tors, including age, gender, ethnicity, education, and presence of personality disorders that affect risk, nevertheless, addiction is not usually life-long. Most Viet Nam vets who used drugs (about 90%) stopped after their return. The dopamine receptors influenc­ ing predisposition to drug use are likely controlled not only by genetic factors, but also by environmen­ tal factors, including social stress.73

It has long been known that early environment plays a role even in the development of morphine self-administration in animals.74 Childhood trauma and neglect have been shown to affect the course of neurological development of the brain as the circuits involved in reward anticipation and emotional regu­ lation are changed.75 The final configuration of the mammalian brain is due to sculpting by experience during development and is particularly malleable during periods of neural development. Childhood patterns of personality development become en­ trenched due to neuronal plasticity and can underlie depression and anxiety disorders.76

In a review of the effects of maltreatment and maternal deprivation on the brain, developmental neuropsychiatrist Martin Teicher asserts, "Maltreat­ ment-related childhood adversity is the leading pre­ ventable risk factor for mental illness and substance abuse."77 Maltreatment alters brain development and affects the structure of prefrontal and orbitofrontal cortical areas, amygdala, and hippocampus which are involved in, among other things, emotional regu­ lation and anticipation of rewards — things that are crucial for avoiding addiction. It is also associated with reduced response to anticipated rewards in parts of the striatum, perhaps leading to enhanced risk for addiction.

The well-known research by John Bowlby and Mary Ainsworth, dating from the 1950s, showed that in order to thrive infants must not only be fed, but must also be in an emotionally satisfying, nurturing rela­ tionship with a stable caregiver in order to develop emotional regulation.78 Addiction could thus be seen as an attachment disorder with attempts at self­ repair in traumatized individuals.79 Self-medication may thus represent an adaption to uncontrollable environmental factors that leads to loss of stabil­ ity, loss of relationships, and loss of self. The basic circuitry for romantic love and attachment, which is evolutionarily prepared for survival of the spe­ cies, includes and overlaps the circuitry co-opted by drugs, particularly opiates; and dopamine is also a major contributor to pair bonding in animals. Augustine, too, according to his own account in Confessions, suffered childhood abuse.

In order to fully understand the addiction crisis, indi­ vidual stress and trauma must also be located in a wider social context. Peer use is one of the strongest

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predictors for adolescent use of alcohol. According to addiction specialist Gabor Mate, adolescents whose primary relationships are with peers do not eas­ ily learn emotional attunement with others because their peers are equally emotionally immature and cannot model appropriate emotional control. A child's lack of emotional attunement with her care­ giver is exacerbated by the lack of support given to the mother by the extended family, tribe, or commu­ nity. Sociologist Peter Berger claims society, created by humans, acts back on human creators who then become the objectified products of society, often los­ ing individual identity in the process.80 This entails a form of self-objectification that forces individuals to construct their own identity. As the framework of tradition and the support of known community are diminished in modern society, individuals become isolated from their traditional base and social roles.81 The mechanisms of social dislocation foster addic­ tion as families are uprooted, and people turn inward because they no longer feel connected.82 Socioeconomic status in humans and animals has been correlated with D2/D3 receptor availability in the striatum; and, as seen above, density of these receptors is lower in addicted humans, although the causal relationship here is unclear.83

When given a choice between cocaine and food, or cocaine and sweetened water or milk, most primates and rats choose the tasty substance, even when it is nonnutritive.84 Self-administration by animals in bare cages pressing levers for intravenous drugs might, in fact, be partly a function of boredom and lack of choice. While boredom and loneliness are com­ mon in dislocated individuals, the greater problem in modern culture is loss of meaning. Psychiatrist Viktor Frankl asserted in 1946 that addiction along with depression and aggression are due to a feel­ ing of emptiness and meaninglessness he called the "existential vacuum."85 External substances provide focus and identity for individuals who lack self- identity and a sense of control over their otherwise uncontrollable lives. While social conditions are not responsible for addiction in any one individual, they lower the playing field for all, and the vulnerable succumb as they seek to temporarily fill the excruci­ ating void.

Social and Cultural Factors Although much of the medical model has been largely confirmed, it does not always take social con­

text into account. The concept of addiction as disease is reified, according to sociologist Robert Granfield, by insisting that individuals are sovereign entities able to make choices apart from cultural context.86 As he wryly notes, addiction is not an equal opportunity disease; some individuals are more vulnerable than others. Those constrained at the bottom of the social order have less choice to "just say no."

In a historical analysis of addictions, Bruce Alexander argues that prevalence tends to wax and wane, with periods of social chaos, such as the decline of the Greek and Roman empires, characterized by addic­ tive behaviors.87 Plato argued that the main cause of alcohol abuse in Greece was the structure of society itself. In what Plato called "just societies," addic­ tion is rarely problematic, but in tyrannical societies almost everyone succumbs. Alcoholism, Alexander claims, was also a serious problem in the declining Roman Empire as evidenced by Augustine's descrip­ tion in Confessions of his mother's early behavior.

The present period is also a time of social chaos and inequality. The economically depressed regions of the US South and Appalachia are among the most drug- afflicted areas. While not dealing specifically with addiction, J.D. Vance's H illb illy Elegy sheds light on the problems caused by community disruption and dislocation of families.88 A study on mortality rates in the US shows that rates among white working-class males without tertiary education are unexpectedly rising, while they continue to decrease among better educated males, white females, and nonwhite indi­ viduals.89 The authors of this study assert that the increase is due to alcohol- and drug-related deaths plus suicide—diseases of despair. Indeed, addiction has become a worldwide problem as the UN esti­ mates that 5% of adults worldwide used illicit drugs in 2014, and 29 million suffer from drug use dis­ orders. Alcohol, tobacco, and illicit drug use account for 12% of worldwide mortality.90

Technology and consumerism tend to interact in a complexity of ways to produce, sustain, and in turn be supported by substance use. Opiates were adver­ tised and mass marketed in patent medicines in the late nineteenth and early twentieth centuries, allow­ ing them to become acceptable to the public at that time. For example, the evangelical reformer William Wilberforce used the tincture of opium known as laudanum daily for 45 years, ostensibly for stom­ ach pain. The fentanyl crisis is partly iatrogenic

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due to physician overprescription of opioid pain medication. Oxycontin makers indulged for profit in fraudulent claims about the nonaddictiveness of their products.91 Modern advertising is complex, potentially ambiguous, and affects all of us. It is well known that the tobacco industry continued to relent­ lessly promote cigarettes even after evidence showed them to be addictive. A 1979 report for Reynolds Tobacco discussed industry plans to enlist the ven­ erable sociologist Peter Berger in their campaign against antismoking publicity.92 In 1991 Berger pro­ duced a report, paid for by Philip Morris, in which he appealed to personal liberty to smoke, arguing that antismoking publicity would discourage liberty to smoke, in spite of the known health and social costs of smoking.93 Arguing in favor of freedom of choice, some politicians continue to speak out against big government regulation of the tobacco industry, but they, in contrast, reject legalization of less-addicting cannabis. The point here is that social, economic, and political factors beyond the control, and sometimes even awareness, of the individual play definite roles in the choice of addictive substance.

Harm reduction policies of providing safe injection sites, needles, Narcan kits, and methadone have been controversial among those who see them as exchang­ ing one opioid for another or as encouraging addicts to continue their habits without consequence. The continued use and development of overdose rever­ sal methods such as naloxone; use and development of methadone and other treatment drugs; and development of alternative medications, includ­ ing cannabinoids, to relieve pain are supported by Francis Collins and his colleagues at the National Institutes of Health (NIH).94 Daniel Mallinson, in this issue, presents policy options for both governments and the church in light of both evidence-based sci­ ence and social ethics.95 Catholic scholar Irene Pettus points out the harms that overzealous Christian atti­ tudes have inflicted on drug abusers, as well as on those in chronic and terminal pain who cannot access controlled medicines.96 In her view, churches that hold attitudes of rejecting not only drug users but also harm reduction, have damaged individuals and groups when they ought instead to play a prophetic role, ministering to the marginalized and criminal­ ized. She reminds us that pain-reducing opiates are largely unavailable to non-Western people, even for terminal illness, partly because of policies based on fear of addiction.

Meaning vs. Despair: Restless Hearts At one time addiction was seen as a moral or spiritual problem, rather than as a physical problem. Addicts were counselled to find moral and spiritual strength to just abstain. Turning aside from the view of uni­ versal sinfulness, AA tends to classify the alcoholic as the victim of a disease yet within a framework that has moral and spiritual implications.97 Not all agree that AA is the most effective form of treatment, but it does work for many, partly because members develop new habits through the support of a strong social network which provides unconditional love and grace no matter how many times they relapse. Of course, support, community, love, and grace are what we should also expect to find within the body of Christ. Social support itself produces natural levels of dopamine, and treatments that provide individu­ als the slow release of dopamine associated with social support rather than supraphysiologic bursting, do seem to show the greatest promise. In particular, the various 12-step programs that utilize continued social support can be combined with medical treat­ ments and cognitive therapy.98 Kent Dunnington, in this issue, sees AA as the best recovery regimen because it aims for a humble reconstitution of the self in the face of the challenges of accepting one's own guilt, shame, and failure while building a new iden­ tity.99 Addicts often lack the self-identity needed to trust or invest in their future self. Its development, however, is undercut by guilt, shame, and failure. The admission of powerlessness over alcohol and the need to cast one's self on a higher power reflect how difficult it is for prideful creatures to ask for grace. Dunnington avers that 12-step programs allow addicts to see self-hood as grace received, by learn­ ing to the rest in the unconditional love of others.

Nevertheless, AA leads to a theological challenge — one can either recognize the Creator as revealed in Jesus Christ, or define AA's "higher power" as one likes, thereby turning one's life over to an essentially self-created divinity.100 Acknowledging the pres­ ent emphasis on widespread behavioral addictions, Linda Mercadante asks if AA's insistence on total abstinence is a new form of effortful Pelagianism. Previously we were all sinners; now we are all dis­ eased. She points out that addiction and sin are fellow travelers, but not to be equated. This conclusion is echoed in this issue by Janet Warren reminding us

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A rtic le Addiction: Diseased Brain, Divided Will, or Restless Heart?

that we all do need development of our self-narra­ tive, because we all face difficulty in acceptance of our guilt, shame, and failures.101

In Confessions Book X, Augustine describes his sexuality, need for love, and need for adulation in terms reminiscent of behavioral addictions. On becoming bishop, he even refused to allow women to enter his residence.102 He also describes his post­ conversion attempts to not enjoy the taste of food or the music of hymns, seemingly replacing his earlier addictions with what psychologist Bruce Alexander considers moralistic obsession. The ten­ dency to merely replace one addiction with another is common, and as stated above, comorbidity is high. Although AA's cofounder Bill Wilson gave up alcoholism, he struggled as a chain smoker until his death from smoking-related emphysema. Alexander opines that Augustine cured his addiction by adopt­ ing a different, more preferable and healthier, form of addiction that provided him with both social sup­ port and ecstatic experience. A valid question here might be if addiction to religion is possible. Religion can become, like addiction, just another way to gain control of one's life. Dunnington notes that addiction to God is indeed possible if religion is grounded in a desire to control God.103 True submission recognizes that even our relationship with God is possible only through grace —in thankfully accepting who we are and accepting God's grace.

Paul's dilemma in Romans 7:15-19 illustrates the moral problem of willing to do one thing, but doing the opposite. Morality has to do with actions, right and wrong, whereas spirituality has to do with the intent of the heart and openness to God's action in one's life (Rom. 8:1-8). Rather than a form of control­ ling life by means of religion, spirituality involves relationship with God. True relationship occurs in freedom rather than self-abnegation, honestly accept­ ing that we are less than what we wish we were. We cannot control our lives or God's opinion of us, but we must accept grace and unconditional love.

Habitual substance abuse changes circuits in the brain and decreases frontal cortical activity because epigenetic changes are fostered by habitual sub­ stance abuse. Habit formation provides one of many examples of how the mind and the brain in mutual relationship grow together and shape each other. An addict becomes more and more trapped in a vicious spiral because repetition of a behavior creates path­

ways in the brain like ruts in an unpaved road. On the other hand, cortical thickness can be physically increased through meditation, and studies have shown that prayer also affects the brain.104 Thus spiritual disciplines can form habits that enable us to become progressively more of what God intends. As new habits are formed, step by small step, old path­ ways in the brain become progressively less activated and newer pathways are gradually strengthened. Functional imaging has shown that rational cogni­ tive strategies that lead to reduction of craving for both food and nicotine can produce activation in the prefrontal-striatal pathway, as well as reduced acti­ vation in the ventral striatum.105 Imaging studies also show that, even though addiction results in loss of grey matter in the frontal cortex, the volume of grey matter in the frontal pathways increases again after months or years of abstinence.106 The brain is always changing in response to the stimulation it receives. New synaptic growth can allow us to renew our minds. Spiritual disciplines can form new habits. Over time, perhaps, relationship with God may even reverse the neural damage done by abusive relation­ ships with a parent or spouse.

Recovery, however, can be slow because it requires repeated instantaneous decisions to resist craving in spite of competition between the striatal habit sys­ tem and the frontal control system. The competition for activation will replay again and again, requiring a long series of moment by moment choices. Drugs such as buprenorphine or methadone can make each decision point a little easier by satisfying the ven­ tral striatum's craving mechanism. Each decisive moment of temptation, however, will contain a mea­ sure, sometimes very small, of free will with which one can grasp the proffered grace. We must avoid both Pelagian perfectionism of moral responsibil­ ity, and Manichean determinism of external factors, while recognizing that we are surrounded at each moment by God's prevenient grace reaching out to enable choices as we reach out in return. Paul's injunction in Romans 12:2 to be transformed by the renewal of the mind is intended for all of us, not just addicts, and it extends by the Spirit's gracious work over our entire lifetime. A

Notes T. Gomes, et al., "The Burden of Opioid-Related Mortality in the United States," JAMA Network Open 1, no. 2 (2018): el80217, doi:10.1001 /jamanetworkopen.2018.0217.

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2National Institute on Drug Abuse Blog Team, "Tobacco, Nicotine, & E-Cigarettes," accessed April 20,2017, https:// teens.drugabuse.gov/drug-facts/tobacco-nicotine-e -cigarettes.

’World Health Organization, WHO Report on the Global Tobacco Epidemic: Tire MPOWER Package (Geneva: WHO, 2008).

4The National Institute on Drug Abuse (NIDA) defines addiction as "characterized by compulsive drug seeking and use, despite harmful consequences." The American Psychiatric Association in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5 (Arlington, VA: American Psychiatric Association, 2013) refers to "sub­ stance use disorders" rather than addiction. See NIDA, "Drug Misuse and Addiction," in Drugs, Brains, and Behav­ ior: The Science of Addiction, July 20, 2018, accessed August 22, 2018, https://w w w .drugabuse.gov/publications / drugs-brains-behavior-science-addiction/ drug-abuse -addiction.

“The medical model is supported by researchers at NIDA, e.g., Nora D. Volkow, George F. Koob, and A. Thomas McLellan, "Neurobiologic Advances from the Brain Dis­ ease Model of Addiction," New England Journal of Medicine 374, no. 4 (2016): 363-71; and Nora D. Volkow and George Koob, "Brain Disease Model of Addiction: Why Is It So Controversial?," Lancet Psychiatry 2, no. 8 (2015): 677-79. The model is disputed by, e.g., Wayne Hall, Adrian Carter, and Cynthia Forlini, "The Brain Disease Model of Addic­ tion: Is It Supported by the Evidence and Has It Delivered on Its Promises?," Lancet Psychiatry 2, no. 1 (2015): 105-10.

6For example, Volkow, Koob, and McLellan, "Neurobio­ logic Advances"; Joseph Frascella et al., "Shared Brain Vulnerabilities Open the Way for Nonsubstance Addic­ tions: Carving Addiction at a New Joint?," Annals of the N.Y. Academy of Sciences 1187 (2010): 294-315; and William M. Struthers, Wired for Intimacy: Hoio Pornography Hijacks the Male Brain (Downers Grove, IL: InterVarsity Press, 2009).

7Kent Dunnington, Addiction and Virtue: Beyond the Mod­ els of Disease and Choice (Downers Grove, IL: InterVarsity Press, 2011); Bruce K. Alexander, The Globalization of Addic­ tion: A Study in Poverty of the Spirit (Oxford, UK: Oxford University Press, 2008); and Gabor Mate, In the Realm of Hungry Ghosts: Close Encounters with Addictions (Berkeley, CA: North Atlantic Books, 2010).

“Discussed in Judith Toronchuk and George F. R. Ellis, "Affective Neuronal Selection: The Nature of the Primor­ dial Emotion Systems," Frontiers in Psychology 3 (2012): article 589.

9Nora D. Volkow and Marisela Morales, "The Brain on Drugs: From Reward to Addiction," Cell 162, no. 4 (August 13, 2015): 712-25, http://dx.doi.org/10.1016 /j.cell.2015.07.046.

’“David J. Nutt et al., "The Dopamine Theory of Addiction: 40 Years of Highs and Lows," Nature Reviews Neuroscience 16, no. 5 (2015): 304-12; and Aldo Badiani et al., "Addic­ tion Research and Theory: A Commentary on the Surgeon General's Report on Alcohol, Drugs, and Health," Addic­ tion Biology 23 (January 23,2018): 3-5.

’’Neurotransmitter receptors are proteins embedded in neural membranes to which transmitters briefly bind. Transporters are embedded proteins which actively move transmitters across membranes.

12Kent C. Berridge and Terry E. Robinson, "Parsing Reward," TRENDS in Neurosciences 26, no. 9 (2003): 507-13.

’’Nora D. Volkow, Joanna S. Fowler, and Gene-Jack Wang, "The Addicted Human Brain: Insights from Imaging Studies," The Journal of Clinical Investigation 111, no. 10 (2003): 1444-51.

14Volkow and Morales, "Brain on Drugs." ,5MDMA ("Ecstasy" or "Molly") has properties similar to both methamphetamines and hallucinogens. "Bath salts" are synthetic cathinones (found in the khat plant) with stimulant properties.

16R. Christopher Pierce and Vidhya Kumaresan, "The Meso- limbic Dopamine System: The Final Common Pathway for the Reinforcing Effect of Drugs of Abuse?," Neurosci­ ence and Biobehavioral Reviews 30, no. 2 (2006): 215-38.

17GABA stands for y-amino butyric acid, the most common inhibitory transmitter in the brain. It binds with two basic types of receptors, GABAa and GABAb.

’“Nutt et al, "The Dopamine Theory"; and Badiani et al., "Addiction Research and Theory."

’“Dopamine has at least five types of receptors (D1 to D5) with somewhat different properties.

20Volkow and Morales, "Brain on Drugs." 21 The actual effect of opioids on the dopamine system is still

somewhat disputed according to Badiani et al., "Addic­ tion Research and Theory."

“The dorsal raphe is involved in emotion, perhaps link­ ing addiction and mood. Glutamate is the most common excitatory transmitter in the brain.

’’’Serotonin (5-HT) has at least sixteen subtypes of receptor. 24This material is reviewed in Pierce and Kumaresan, "The

Mesolimbic Dopamine System." “NIDA, "Prescription Opioids and Heroin," National

Institute on Drug Abuse website, posted January 17, 2018, accessed April 9, 2018, https://www.drugabuse .g o v /p u b lica tio n s /re se a rc h -re p o rts /re la tio n sh ip -between-prescription-drug-heroin-abuse/prescription -opioid-use-risk-factor-heroin-use; and Francis S. Collins, Walter J. Koroshetz, and Nora D. Volkow, "Helping to End Addiction Over the Long-Term: The Research Plan for the NIH HEAL Initiative," Journal of the American Medical Association 320, no. 2 (2018): 129-30, doi:10.1001 /jama.2018.8826.

26U.S. Department of Justice, Drug Enforcement Admin­ istration, "2016 National Drug Threat Assessment Summary," November 2016, 65-70, https://www.dea .g o v /s ite s /d e fa u lt/f ile s /2018-07/DIR-001-17_2016 _NDT A_Summary .pdf.

27CBC News, "More Than 1,420 People Died of Illicit-Drug Overdoses in B.C. in 2017, The 'Most Tragic Year Ever': Coroner," posted January 31, 2018, accessed March 25, 2018, http://www.cbc.ca/news/canada/british-columbia / overdose-deaths-bc-2017-1.4511918.

“There are three basic types of opioid receptors: |i, k, and 5. k receptors in NAc bind with endogenous dynorphin and play a role in withdrawal as discussed below. Opi­ oid antagonists such as naltrexone are somewhat effective in reducing both alcohol and nicotine use, confirming the involvement of opioid receptors in the rewarding effect of these drugs.

29Naomi Eisenberger, "The Pain of Social Disconnection: Examining the Shared Neural Underpinnings of Physi­ cal and Social Pain," Nature Reviews Neuroscience 13, no. 6 (2013): 421-34; and Naomi Eisenberger, "The Neural Bases of Social Pain: Evidence for Shared Representa­ tions with Physical Pain," Psychosomatic Medicine 74, no. 2 (2012): 126-35.

Volume 70, Number 4, December 2018 229

A r t ic le A ddiction: D iseased Brain, D iv ided W ill, or Restless H eart? MJason P. Connor, Paul S. Haber, and Wayne D. Hall, "Alco­

hol Use Disorders," Lancet 387, no. 10022 (2016): 988-98. 3ipierce and Kumaresan, "The Mesolimbic Dopamine

System." 32Linda Spear, "Effects of Adolescent Alcohol Consumption

on the Brain and Behavior," Nature Reviews Neuroscience 19, no. 4 (2018): 197-214.

33See H. Valerie Curran et al., "Keep Off the Grass? Cannabis, Cognition and Addiction," Nature Reviews Neuroscience 17, no. 5 (2016): 293-306 for review of the research literature.

^M. Colizzia et al., "Effect of Cannabis on Glutamate Sig­ nalling in the Brain: A Systematic Review of Human and Animal Evidence," Neuroscience and Biobehavioral Reviews 64 (2017): 359-81.

35Curran et al., "Keep Off the Grass?"; and Valentina Lorenzetti, Nadia Solowij, and Murat Yiicel, "The Role of Cannabinoids in Neuroanatomic Alterations in Cannabis Users," Biological Psychiatry 79, no. 7 (2016): el7-e31.

“ Reviewed in Lorenzetti, Solowij, and Yiicel, "The Role of Cannabinoids."

37Francesca M. Filbey et al., "Long-Term Effects of Mari­ juana Use on the Brain," Proceedings of the National Academy of Sciences 111, no. 47 (2014): 16913-18.

“ Curran et al., "Keep Off the Grass?"; and Lorenzetti, Solowij, and Yiicel, "The Role of Cannabinoids."

39Catalina Lopez-Quintero et al., "Probability and Pre­ dictors of Transition from First Use to Dependence on Nicotine, Alcohol, Cannabis, and Cocaine: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)," Drug and Alcohol Dependence 115, no. 1-2 (2011): 120-30.

40Eric J. Nestler et al., eds., Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3rd ed. (New York: McGraw-Hill Medical, 2015), 378, 385.

41Fernando Berrendero et al., "Neurobiological Mecha­ nisms Involved in Nicotine Dependence and Reward: Participation of the Endogenous Opioid System," Neuro­ science and Biobehavioral Reviews 35, no. 2 (2010): 220-31; Shiroh Kishioka et al., "Nicotine Effects and the Endog­ enous Opioid System," Journal of Pharmacological Science 125 (2014): 117-24; and Nestler et al., eds., Molecular Neu­ ropharmacology, 385-86.

42Dynorphin is an endogenous opiate that binds to k opiate receptors and is hypothesized to mediate negative emo­ tional states.

43See Frascella et al., "Shared Brain Vulnerablities." 44Toronchuk and Ellis, "Affective Neuronal Selection." 45Reviewed in Daniela S. S. Lobo and James L. Kennedy,

"Genetic Aspects of Pathological Gambling: A Complex Disorder with Shared Genetic Vulnerabilities," Addiction 104, no. 9 (2009): 1454-65.

46Dardo Tomasi and Nora D. Volkow, "Striatocortical Path­ way Dysfunction in Addiction and Obesity: Differences and Similarities," Critical Reviews in Biochemical and Molec­ ular Biology 48, no. 1 (2013): 1-19.

47Gene-Jack Wang et al., "Similarity between Obesity and Drug Addiction as Assessed by Neurofunctional Imaging: A Concept Review," Journal of Addiction Disorders 23, no. 3 (2004): 39-53.

“ Volkow et al., "Neurobiologic Advances." “ Struthers, Wired for Intimacy. “ Matthias Brand, Kimberly S. Young, and Christian Laier,

"Prefrontal Control and Internet Addiction: A Theoretical Model and Review of Neuropsychological and Neuroim­ aging Findings," Frontiers in Human Neuroscience 8 (2014):

article 375; and Todd Love et al., "Neuroscience of Inter­ net Pornography Addiction: A Review and Update," Behavioral Sciences 5 (2015): 388-433.

51Kenneth Blum et al., "The Addictive Brain: All Roads Lead to Dopamine," Journal of Psychoactive Drugs 44, no. 2 (2012): 134-43.

52Eric Nestler, "Cellular Basis of Memory for Addiction," Dialogues in Clinical Neuroscience 15, no. 4 (2013): 431-43.

53Robin Rylaarsdam, "The Genetics of Addiction," Perspec­ tives on Science and Christian Faith 70, no. 4 (2018): 232-41.

^Catherine H. Demers, Ryan Bogdan, and Arpana Agrawal, "The Genetics, Neurogenetics and Pharmacogenetics of Addiction," Current Behavioral Neuroscience Reports 1, no. 1 (2014): 33-44.

55K. K. Blum et al., "The D2 Dopamine Receptor Gene as a Determinant of Reward Deficiency Syndrome," Journal of the Royal Society of Medicine 89, no. 7 (1996): 396-400; also Blum, "The Addictive Brain."

“Volkow and Morales, "Brain on Drugs." 57Connor, Habor, and Hall, "Alcohol Use Disorders." “ Augustine, The Confessions, Part 1, Vol. 1, ed. John E.

Rotelle, O.S.A. (New York: New City Press, 1997), Book VIII.9.21, 201.

“Daniel Kahneman, Thinking, Fast and Slow (New York: Farrar, Straus and Giroux, 2011), 20-30.

“ However, some researchers no longer consider tolerance and withdrawal to be necessary components of addiction. See Nestler et al., Molecular Neuropharmacology, 380,381.

“ Barry Everitt and Trevor Robbins, "From the Ventral to the Dorsal Striatum: Devolving Views of Their Roles in Drug Addiction," Neuroscience and Biobehavioral Reviews 37, no. 9, Pt. A (2013): 1946-54.

“George F. Koob and Michel Le Moal, "Addiction and the Brain Antireward System," Annual Review of Psychology 59, no. 1 (2008): 29-53; and Nora D. Volkow et al., "Addic­ tion: Beyond Dopamine Reward Circuitry," Proceedings of the National Academy of Sciences USA 108, no. 37 (2011): 15037-42. But see Badiani et al., "Addiction Research and Theory," for a slightly different interpretation.

63Koob and Le Moal, "Brain Antireward System"; George F. Koob, "Negative Reinforcement in Drug Addiction: The Darkness Within," Current Opinion in Neurobiology 23, no. 24 (2013): 559-63; and George F. Koob and Michel Le Moal, "Plasticity of Reward Neurocircuitry and the 'Dark Side' of Drug Addiction," Nature Reviews Neuroscience 8, no. 11 (2005): 1442-44.

“ Erie J. Nestler, Michel Barrot, and David W. Self, "AFosB: A Sustained Molecular Switch for Addiction," Proceedings of the National Academy of Sciences of the United States of America 98, no. 20 (200i): 11042-46.

“ Volkow, Fowler, and Wang, "The Addicted Human Brain"; and Volkow and Morales, "Brain on Drugs." However, Nutt et al., "The Dopamine Theory," take a dif­ ferent view of these data.

“ Marc Lewis, The Biology of Desire: Why Addiction Is Not a Disease (New York: Public Affairs, 2015); and Marc Lewis, "Addiction and the Brain: Development Not Disease," Neuroethics 10, no. 1 (2017): 7-18.

“ Everitt and Robbins, "From the Ventral to the Dorsal Striatum."

“ Lewis, Biology of Desire, 127. “ Augustine, Confessions, Book IX.12.32,232. 70B. J. Casey, "Beyond Simple Models of Self-Control to

Circuit-Based Accounts of Adolescent Behavior," Annual Revieiu of Psychology 66 (2015): 295-319.

230 Perspectives on Science and Christian Faith

Judith A. Toronchuk

’’’Lauren M. Reynolds et a l, "DCC Receptors Drive Pre­ frontal Cortex Maturation by Determining Dopamine Axon Targeting in Adolescence," Biological Psychiatry 83, no. 2 (2018): 181-92.

72Lopez-Quintero et al., "Probability and Predictors." 73Volkow and Morales, "Brain on Drugs." 74Bruce K. Alexander, Robert B. Coambs, and Patricia F.

Hadaway, "The Effect of Housing and Gender on Mor­ phine Self-Administration in Rats," Psychopharmacology 58, no. 2 (1978): 175-79.

75Martin H. Teicher and Jaqueline A. Samson, "Annual Research Review: Enduring Neurobiological Effects of Childhood Abuse and Neglect," Journal of Child Psychol­ ogy and Psychiatry 57, no. 3 (2016): 241-66; also Frascella et al., "Shared Brain Vulnerabilities."

76Lewis, Addiction and the Brain. 77Martin H. Teicher et al., "The Effects of Childhood Mal­

treatment on Brain Structure, Function and Connectivity," Nature Reviews Neuroscience 17, no. 10 (2016): 652-66.

78John Bowlby and Mary Ainsworth, Attachment and Loss (New York: Basic Books, 1969).

79Matb, Hungry Ghosts, 162-201. 8°peter Berger, The Sacred Canopy: Elements of a Sociological

Theory of Religion (New York: Doubleday, 1967). 8,Craig Gay, The Way of the (Modern) World: Or Why It's

Tempting to Live As If God Doesn't Exist (Grand Rapids, MI: Eerdmans, 1998), 197.

82Bruce K. Alexander, "Addiction: Hopeful Prophecy from a Time of Despair," April 2017, accessed June 29, 2017, http://Www.brucekalexander.com/articles-speeches/289 -addiction-a-hopeful-prophecy-from-a-time-of-despair.

“Corinde E. Wiers et al., "Socioeconomic Status Is Associ­ ated with Striatal Dopamine D2/D3 Receptors in Healthy Volunteers but Not in Cocaine Abusers," Neuroscience Let­ ters 617 (2016): 27-31.

84Serge H. Ahmed, "Validation Crisis in Animal Models of Drug Addiction: Beyond Non-disordered Drug Use toward Drug Addiction," Neuroscience and Biobehavioral Reviews 35 (2010): 172-84.

85Viktor Frankl, Man's Search for Meaning: An Introduction to Logotherapy (New York: Pocket Books, 1963), 49, 63.

“ Robert Granfield, "Addiction and Modernity: A Com­ ment on a Global Theory of Addiction," Nordic Studies on Alcohol and Drugs 44 (2004): 29-34.

87Alexander, Globalization of Addiction; and Alexander, "Hopeful Prophecy."

“J. D. Vance, Hillbilly Elegy: A Memoir of a Family and Culture in Crisis (New York: HarperCollins, 2016), Kindle.

89Anne Case and Angus Deaton, "Mortality and Morbid­ ity in the 21st Century," in Brookings Papers on Economic Activity: Spring 2017, ed. Janice Eberly and James H. Stock (Washington, DC: Brookings Institute, 2017), 397-476.

‘“United Nations Office on Drugs and Crime, World Drug Report (Vienna: United Nations Publication, 2016).

91For example, Kelly Crowe, "New Questions about Old Canadian Study Foreshadowing Opioid Crisis," CBC News, June 2, 2018, http://www.cbc.ca/news/health / second-opinionl80602-l .4687687.

92G. Berman, "Social Costs, Social Values," RJ Reynolds Records, September 9,1979, accessed July 3, 2017, h ttp :// industrydocum ents.library .ucsf.edu/tobacco/docs /xhhn0088.

93Peter L. Berger, "The Anti-smoking Movement in Global Perspective," Philip Morris Records, 1991, accessed July 3,

2017, http://industrydocuments.library.ucsf.edu/tobacco /docs/nxvd0110.

94Collins et al., "Helping to End Addiction"; and Nora Volkow and Francis Collins, "The Role of Science in Addressing the Opioid Crisis," The New England Journal of Medicine 377, no. 4 (2017): 391-94.

95Daniel J. Mallinson, "Tackling Addiction: A Case for Drug Policy Reform Based on Science and Christian Ethics," Perspectives on Science and Christian Faith 70, no. 4 (2018): 264-74.

“Katherine Irene Pettus, "Churches and International Pol­ icy: The Case of the 'War on Drugs/ A Call to Metanoia," Philosophia Reformata 81, no. 1 (2016): 50-69.

97Linda Mercadante, Victims and Sinners: Spiritual Roots of Addiction and Recovery (Louisville, KY: Westminster John Knox, 1996).

98Dunnington, Addiction and Virtue; and Kent Dunnington, "Recovery and the Humble Reconstitution of the Self," Perspectives on Science and Christian Faith 70, no. 4 (2018): 242-51.

"Dunnington, Addiction and Virtue. ’"Linda Mercadante, "Sin and Addiction: Conceptual Ene­

mies or Fellow Travelers?," Religions 6, no. 2 (2015): 614-25. 101E. Janet Warren, "'I Do Not Do What I Want': Common­

alities in Addiction and Sin," Perspectives on Science and Christian Faith 70, no. 4 (2018): 252-63.

’"Alexander, Globalization of Addiction, 288-92. ’"Dunnington, Addiction and Virtue, locations 1715-803. ’“ Many examples include Sarah W. Lazar et al., "Medita­

tion Experience Is Associated with Increased Cortical Thickness," Neuroreport 16, no. 17 (2005): 1893-97; and Omar Singleton et al., "Change in Brainstem Gray Matter Concentration Following a Mindfulness-Based Interven­ tion Is Correlated with Improvement in Psychological Well-Being," Frontiers in Human Neuroscience 8 (2014): 33, http ://doi.org/10.3389/ fnhum.2014.00033.

105Hedy Kober et al., "Prefrontal-Striatal Pathway Under­ lies Cognitive Regulation of Craving," Proceedings of the National Academy of Sciences 107, no. 33 (2010): 14811-16.

106Colm G. Connolly et al., "Dissociated Grey Matter Changes with Prolonged Addiction and Extended Absti­ nence in Cocaine Users," PLoS ONE 8, no. 3 (2013): e59645, https: / / doi.org/10.1371 / journal, pone.0059645.

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